According to the statistics of the World Health Organization (WHO), it is reported that the world death rate for cardiovascular diseases in 1999 was 30% or greater, and the cardiovascular diseases will be the first ranking diseases causing death in developed countries in year 2010, while the increase rate of the diseases is high particularly in Asian countries including Japan, South Korea and the like. This is speculated to be attributable to an increase in the risk factors for coronary artery diseases, as a result of the coming aged society, changes in the dietary habits, and the like.
Endothelial dysfunction is the main mechanism which induces an extensive range of cardiovascular diseases, including hypertension, arteriosclerosis, hyperlipidemia, diabetes mellitus, obesity and the like (Brunner H. et al., J. Hypertens., 2005, 23:233-246), since the discovery of abnormal relaxation of blood vessels in hypertensive patients in 1990 (Panza J A et al., New England Journal of Medicine, 323:22-27, 1990). Endothelial cells are epithelial cells lining along the cavities of blood vessels and lymph vessels, and their main function is to produce vasodilators and vasodilator mediators to regulate the vascular tone as well as the structure.
A cardiovascular disease is a disease starting in the form of initial endothelial dysfunction and finally resulting in abnormality in the heart and vascular system. The name is a generic term for a group of abnormalities in the heart and blood vessels, including, but not limited to, arteriosclerosis, hypertension, hyperlipidemia, coronary artery diseases (heart attack), cerebrovascular diseases (cerebral stroke, dementia), peripheral vascular diseases, arrhythmia, cardiac failure, congestive heart diseases, myocardial diseases, and the like.
As for principal factors for the manifestation of cardiovascular diseases, there are known a variety of factors such as genetic factors, lifestyle, and complications of diabetes mellitus. From the standpoint of modern medicine, increases in the reactive oxygen species (ROS) and vascular oxidative stress as a result of an increase in the activity of NADPH oxidases, and a decrease in nitric oxide due to a decrease in the activity of endothelial-type nitric oxide synthase (eNOS), are known as principal factors. Nitric oxide which is produced by endothelia-type nitric oxide synthase, is a potent vasorelaxant factor, and also plays a critical role in the overall homeostatic regulation of the cardiovascular system by inhibiting platelet aggregation, proliferation of vascular muscle cells, vascular adhesion of monocytes, and expression of arteriosclerosis-associated proteins (Forstermann et al., Circulation, 113:1708-1714, 2006). However, an increase, caused by a number of factors, in the activity of NADPH oxidases which are in charge of the generation of active oxygen species in the blood vessels, leads to a decrease in the production of nitric oxide [Gryglewski et al., Nature, 320:454-456, 1986; Paravicini et al., Circulation Research, 91:54-61, 2002; Dusting et al., Clinical and Experimental Pharmacology and Physiology, 25:S34-41, 1998], and the active oxygen species thus produced bring about regulation of the expression of adhesive molecules [Lo et al., Am. J. Physiol., 264:L406-412, 1993], stimulation of the proliferation and migration of vascular smooth muscle cells (VSMC) [Griendling and Ushio-Fukai, J. Lab. Clin. Med., 132:9-15, 1998], regulation of lipoproteins having oxidizing power, and the like, to thereby cause cardiovascular diseases [Lynch and Frei, J. Lipid Res., 34:1745-1753, 1993]. Furthermore, the increased generation of active oxygen species in the blood vessels due to NAD(P)H oxidases, is associated with the impaired function of endothelial nitric oxide (NO) in patients having clinical risk factors for atherosclerosis and coronary artery diseases. Fundamentally, the generation of active oxygen species brings about contraction of blood vessels [Guzik et al., Cir. Res., 86:E85-90, 2000]. In general, reduction of active oxygen species, suppression of downstream generation of active oxygen species, and induction of the activity of endothelial-type nitric oxide synthase, all through direct inhibition of NAD(P)H oxidases, are recognized as very important targets in the prevention and treatment of cardiovascular diseases [Forstermann et al., Circulation, 113:1708-1714, 2006; Doggrell S A, Drug News Perspect., 17(9) 615-632, 2004; Inoguchi T., Curr. Drug Targets, 6(4):495-501, 2005; Muzaffar S. et al., Trends Cardiovasc Med., 15(8):278-282].
To date, known as the substances inhibiting NAD(P)H oxidases are diphenylene iodonium (DPI) and 4-hydroxy-3-methoxyacetophenone (Apocynin) [Holland J, et al., U.S. Pat. No. 5,902,831]. However, these substances have not been put into commercialization or clinical use because of the problems of toxicity and specificity. Furthermore, as nitric oxide regulators, there are available nitroprusside and nitroglycerine. However, these substances are also put into use only in the cases of emergency such as heart attack, because of the problems of resistance and toxicity in clinical uses.
Meanwhile, Lindera obtusiloba is a deciduous shrub of family Lauraceae. It grows to a height of about 2 to 3 m, and the flowering season is from March to April, while the fruiting season is September. The fruits are pressed to obtain oil, which has been used as a hair oil for women. The plant is called “Ginger Tree” because the plant smells like ginger when the leaves or twigs are plucked off, and is also known as Fool's Camellia or Japanese spicebush. The plant is known to be efficacious in activation of blood, slow twitching of muscle, anti-abscess and the like, and to treat bruises, and swelling and pain due to blood extravasation, and the plant is usually squashed and adhered to the site of wound. The plant is mainly used against stomach ache, and is also used as an antifebrile or a cough medicine. In private practices, leaves and buds of the plant are brewed and taken like tea, as an antifebrile or a cough medicine [Illustrated Book of Korean Plants, by Chang-Bok Lee, 1980; Illustrated Book of Korean Folk Medicines, by Jong-Hee Park, 2005, Encyclopedia of Local Medicines].
In regard to researches on the components of Lindera Obtusiloba, Park, Jong-Chul, et al. (J. Korean Soc. Food Nutr. 1996. 25(1), p. 76-79) isolated quercitrin from the leaves, and hyperoside from the twigs, while Kwon, Hak-Cheol, et al. (Archives of Pharmacal Research, 22, p. 417-422, 1999) isolated actifolin, pluviatiolol, 5,6-dihydromatairesinol, (+)-syringaresinol, 9-O-trans-feruloyl-5,5-dimethoxylariciresinol and the like. The efficacies of the respective isolated components are reported to include cancinocidal action, anti-inflammatory action, and the like (Planta Medica, 69, 610-616, 2003; Archives of Pharmacal Research, 22, p. 417-422, 1999).
However, no disclosure or teaching is given in the above-mentioned literatures, on that an extract of Lindera obtusiloba has effects of suppression of vascular oxidative stress, relaxation of blood vessels and regulation of blood pressure, through inhibition of NADPH oxidases.